Radioactive transition metal stents

ABSTRACT

A radioactive transition metal stent, comprising one or more transition metals, wherein the transition metal stent surface is chemically bound to a radioactive material; and a method for producing the radioactive transition metal stent wherein the radioisotope is chemically bound to, and is uniformly confined to the transition metal stent surface without affecting the metallurgical properties of the transition metal stent is disclosed.

TECHNICAL FIELD

This invention relates generally to intravascular implantation devicesand more particularly to a radioactive transition metal stent, whereinthe stent surface comprises chemically-bound radioisotope, fortherapeutic and diagnostic applications.

BACKGROUND OF THE INVENTION

Intravascular stents have been permanently implanted in coronary orperipheral vessels to prevent restenosis. See, e.g. U.S. Pat. Nos.5,800,507; 5,059,166 and 5,840,009. Trauma or injury to the arterycaused by angioplasty procedures, implantation of stents, atherectomy orlaser treatment of the artery, result in restenosis, i.e., the closureor renarrowing of the artery. Restenosis, a natural healing reaction tothe injury of the arterial wall, begins with the clotting of blood atthe site of the injury, followed by intimal hyperplasia, i.e. the rapidgrowth of the injured arterial tissue through the openings in the stent,and the migration and proliferation of medial smooth muscle cells, untilthe artery is again stenotic or occluded.

However, such stents are not always effective in preventing restenosisand can cause undesirable local thrombosis. A variety of solutions havebeen proposed to minimize these undesirable effects, such as coating thestents with a biocompatible or an anti-thrombotic surface, wherein thestent-surface is seeded with endothelial cells or fibrin, or usingstents as drug delivery devices. See for example, U. S. Pat. Nos.5,800,507;5,059,166; WO 91/12779 and WO 90/13332.

Implanted stents, in conjunction with endovascular irradiation, arebelieved to prevent restenosis by alleviating neointimal hyperplasia.The beta-particle emitter, phosphorus-32 (³²P) radioisotope, has beenused as a permanent medical implant. Fischell et al. describe stentsformed from radioactive materials, wherein a radioisotope isincorporated into the stent by physical methods, such as coating,plating, implanting on the exterior surface of the stent; insertinginside the stent; and alloying into the metal from which the stent ismade. Alternatively, a beam of an ionized radioisotope is directed onthe surface of the stent. See U.S. Pat. Nos. 5,059,166, 5,176,617,5,722,984, and 5,840,009. Typically, an ion-implantation method requiresirradiating sublimed red phosphorous (to avoid contamination) for aboutten days to achieve a sufficient concentration of phosphorous-32 (³²P)to obtain radioactivity of 4 to 13 μCi per stent. However, this methodis expensive, requires sophisticated equipment, and the transfer of theradioactive source from the nuclear reactor to the ion-implanter to themedical site adversely affect the short half-life of phosphorous-32(³²P) (14.3 days). Additionally, ion-implantation damages the surface ofthe stent, the interstitially implanted phosphorous-32 (³²P) diffusesrapidly and is relatively unstable compared to chemically boundphosphorous-32 (³²P). Moreover, ion-implantation requires beam and/orsubstrate scanning to achieve uniformity, which is difficult to obtainon a radial open-mesh stent. Thus conventional methods result in lowerquality, non-uniform radioactive stents.

Strathearn, et al. describe a process for diffusing chemically boundradioactive ions below the surface of the substrate, wherein diffusionis accomplished by heating the substrate between 300° to 600° C. (U.S.Pat. No. 5,851,315). However, current techniques do not provide forradioactive stents with a radioisotope concentrated at the point ofmaximum tissue penetration, wherein the radioisotope, such asphosphorus-32 (³²P), is chemically bound to and is uniformly confined tothe surface without affecting the metallurgical properties, such asductility and malleability, of the stent. Thus, there is a need forimproved and cost-effective radioactive stents, wherein the radioisotopeis uniformly distributed over the surface and is concentrated at thepoint of maximum tissue penetration.

SUMMARY OF THE INVENTION

The present invention relates to a radioactive transition metal stent,comprising one or more transition metals, wherein the transition metalsurface is chemically bound to a radioactive material; and a method ofproducing the radioactive transition metal stent wherein theradioisotope is chemically bound to and is uniformly confined to thetransition metal surface without affecting the metallurgical propertiesof the stent. Unlike conventional methods, the present method does notrely on the complex techniques described above. Accordingly, the presentinvention provides an improved and cost-effective radioactive transitionmetal metaphosphate stent surface and a method of making the same.

In one aspect, the invention relates to a radioactive transition metalstent comprising one or more transition metals, wherein the transitionmetal surface is chemically bound to a radioactive material, and furtherwherein the transition metal is a single element or an alloy of two ormore transition metals. In a preferred embodiment, the radioactivematerial comprises a phosphorus-32 (³²P) metaphosphate, wherein theradioactivity of the transition metal stent ranges from about 0.1 μCi toabout 100 μCi per stent.

In another aspect, the invention relates to a method of producing aradioactive transition metal stent, comprising one or more transitionmetals wherein the transition metal surface is chemically bound to aradioactive material, comprising:

(i) providing a solution of dehydrated phosphorus-32 (³²P) enrichedmetaphosphoric acid;

(ii) mixing the phosphorus-32 (³²P) enriched metaphosphoric acid with ainert polymer to form an emulsion;

(iii) stabilizing the emulsion;

(iv) immersing a transition metal stent in the stabilized emulsion;

(v) removing the stent from the emulsion; and

(vi) washing and drying the stent to obtain the radioactive transitionmetal metaphosphate stent.

In an alternative embodiment, the stent is further immersed in asuitable non-polar solvent with a low dielectric constant, such asn-hexane, chloroform, carbon tetrachloride, diethyl ether, and the like,to remove the residual polymer. In a preferred embodiment, the non-polarsolvent is n-hexane.

In preferred embodiments, the transition metal is a single element or analloy of two or more transition metals and the inert polymer is apolysiloxane polymer. In another preferred embodiment, the phosphorus-32(³²P) enriched metaphosphoric acid has a radioactivity of about 1 mCi toabout 10,000 mCi per ml and is mixed with a linear polysiloxane polymerto form an emulsion, wherein the emulsion is stabilized at a temperaturebetween 150° C. to about 300° C., and further wherein the stent isimmersed in the emulsion for a duration of between about 10 minutes toabout 180 minutes to yield a transition metal stent metaphosphate havinga radioactivity of about 0.1 μCi to about 100 μCi per stent.

In an alternative embodiment, the transtion-metal stent ismicroscopically roughened prior to immersion or concomitantly in theemulsion. In a preferred embodiment, the transtion-metal stent ismicroscopically roughened in the upper stent surface.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the X-ray photoelectron spectroscopy (XPS) sputterdepth profile for a radioactive stainless steel stent of the invention.

FIG. 2 illustrates the binding energy profile for a radioactivestainless steel stent of the invention.

DETAILED DESCRIPTION

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of chemistry, biochemistry, andmedicine, including diagnostics, which are within the skill of the art.Such techniques are explained fully in the literature. See, e.g.,Principles of Physical Chemistry, Maron, S. H. and Prutton, C. F.,(4^(th) Edition, 1965, The MacMillan Company) and Advanced InorganicChemistry, Cotton, F. A. and Wilkinson, G., (3^(rd) Edition, 1972,Interscience Publishers).

All patents, patent applications, and publications mentioned herein,whether supra or infra, are hereby incorporated by reference in theirentirety.

A. Definitions

In describing the present invention, the following terms will beemployed, and are intended to be defined as indicated below.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an”, and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a transition metal” includes two or more such metals, andthe like.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. The following terms areintended to be defined as indicated below.

As used herein, the terms “transition metal” or “transition element”refers to any element in which the filling of the outermost shell toeight electrons within a periodic table is interrupted to bring thepenultimate shell from 8 to 18 or 32 electrons. Transition elementsinclude, without limitation, scandium, titanium, vanadium, chromium,manganese, iron, cobalt, nickel, copper, zinc, ytterbium, zirconium,niobium, molybdenum, silver, lanthanum, hafnium, tantalum, tungsten,rhenium, rare-earth elements, cerium, praseodymium, neodymium,promethium, samarium, europium, gadolinium, terbium, dysprosium,holmium, erbium, thulium, yttrium, lutetium, and rhodium.

As used herein, the term “alloy” refers to a mixture of two or moretransition metals. Examples of alloys include, but are not limited to,stainless-steel type 316, stainless-steel type 316L, nitinol (anickel-titanium alloy), elgiloy (a cobalt-nickel alloy), allcommercially available from, e.g. Alan Steel & Supply Co., Redwood City,Calif.; Carpenter Technology Corp., Hayward, Calif.; Shape MemoryApplications, Inc., Santa Clara, Calif. and Elgiloy Ltd. Partnership,Elgin, Ill.

As used herein, the term “stent” refers to a metallic surface, whereinthe metal may be any geometrical shape or form, such as round,rectangular, square, cylindrical, flat surfaces, catheters, wires,helically coiled spring, and the like. In a preferred embodiment, themetal may be any material or device used to support a tissue, graft oranastomosis during the healing process. In another preferred embodiment,the stent is in the form of a cylindrical wire.

As used herein, an “inert polymer” refers to a liquid that does notreact with the stent metal or the dehydrated phosphorus-32 enrichedmetaphosphoric acid, and does not cause the soluble phosphorus-32concentration to be reduced. Examples of inert polymers include, but arenot limited to, a linear polysiloxane polymer having a room-temperaturekinematic viscosity of 0.1 to 1000 CS, high temperature oils andlubricants having a flash point below 250° C., preferably a flash pointof between 190°-250° C., and more preferably between 200°-230° C.

As used herein, the term “kinematic viscosity” is defined as the ratiosof viscosity coefficient divided by density. A standard kinematicviscosity unit is a CS.

B. General Methods

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular transitionmetal stents or process parameters as such may, of course, vary. It isalso to be understood that the terminology and examples used herein arefor the purpose of describing particular embodiments of the inventiononly, and are not intended to be limiting.

Although a number of transition metal stents and methods similar orequivalent to those described herein can be used in the practice of thepresent invention, the preferred materials and methods are described.

The invention provides a radioactive transition metal stent and a methodof producing the same. Stents for use with the present invention can beof any useful geometrical shape or form, as described above. Generally,stents have a radial area that may be approximated as half that of acylindrical tube. Thus the surface area of a typical 0.3 cm diameter, 2cm long stent is approximately 2 cm². The length of the stent will varydepending on the particular application and can be as long as 45 mm andas short as 1.5 mm.

Using currently available techniques, a radioactive doped transitionmetal metaphosphate stent may be produced as follows. For example, for a10 nm thick transition metal metaphosphate containing 20% phosphorous,e.g., Me₂(PO₃)₃, having a typical density of 5×10²² atoms/cm³, there area total of 1×10¹⁶ phosphorus atoms/cm². A transition metal metaphosphategrown uniformly on a 2 cm stent as described above, would accommodate2×10¹⁶ phosphorus atoms. The radioactive phosphorus atoms must bepresent in a concentration sufficient to permit efficient transfer ofradioactive atoms from an appropriate chemical source to the stent. Forexample, the ratio of available phosphorus in 0.5 ml anhydrousorthophosphoric acid (H₃PO₄) to that to be incorporated into the stentis approximately 300,000:1. Thus, 1.0 Ci phosphorus-32 enriched acidwill yield a 3.3 μCi phosphorus-32 enriched stent.

Uniform and continuous contact with the stent using such a small volumeof the very viscous orthophosphoric acid is impractical and notfeasible. Thus to obtain a radioactive transition metal stent, whereinthe radioisotope is chemically bound to, and is uniformly confined tothe transition metal surface without affecting the metallurgicalproperties of the stent, it is necessary to increase the effectivecontact area of the stent surface with the orthophosphoric acid, withoutdegrading or reducing the radioactive concentration of the acid. Theinstant invention provides a method wherein the transition metal stentis in uniform and continuous contact with the radioactive metaphosphoricacid. The radioactively enriched acid is suspended in a suitableemulsion, and the transition metal stent is then immersed in thestabilized emulsion to allow a uniform, surface-controlled metaphosphategrowth on the transition metal stent surface. Additionally, more thanone radioactive stent can be produced simultaneously using the method ofthe invention, thus adding to the cost-effectiveness of the radioactivestents.

A procedure for producing a radioactive transition metal stent in whichthe radioisotope is chemically bonded to the transition metal stentsurface is described as follows. In preferred embodiments, thetransition metal is a single element or an alloy of two or moretransition metals and the inert polymer is a polysiloxane polymer.

Metaphosphoric acid (HPO₃), (wherein n=3 or 4) is prepared according toknown procedures. (See The Merck Index, 9^(th) Ed, 1976, page 956).Phosphorus-32 enriched 85% H₃PO₄ is heated in an open vessel at atemperature above 300° C., preferably about 300° C. to about 420° C.,and most preferably about 310° C. to about 350° C.; for approximatelyabout 5 to 50 hours, preferably 20 to 50 hours, and most preferably 20to 30 hours, to yield the metaphosphoric acid having a radioactivity ofabout 1 mCi to about 10,000 mCi per ml, preferably 10 mCi to about 7,000mCi per ml, and more preferably 100 mCi to about 3,000 mCi per ml. Aninert polymer is added to the metaphosphoric acid to form an emulsion,wherein the volume ratio of acid to polymer ranges from about 1:1 toabout 1:500, preferably from about 1:1 to about 1:300, and mostpreferably from about 1:2 to about 1:10. The emulsion is thenstabilized, i.e. equilibrated, with agitation, at about 150-300° C. Atransition metal stent having a thickness of about 10 nm to about 1000nm, preferably about 10 nm to about 700 nm, and more preferably about 10nm to about 500 nm, is completely immersed in the emulsion for about10-120 minutes, preferably 10 to 180 minutes, and most preferably 30 to60 minutes, while being gently agitated so that it is in constantcontact with the acid globules. The stent is then removed from theemulsion, rinsed in boiling deionized water, rinsed again in roomtemperature deionized water, and dried using nitrogen gas. The stent isthen optionally immersed in a suitable non-polar solvent with a lowdielectric constant, such as n-hexane, chloroform, carbon tetrachloride,diethyl ether, and the like, to remove the residual polymer.

The radioactivity of the stent is measured using a suitablebeta-particle counter and readied for permanent or temporaryendovascular implantation, such as cornary, iliac, urethral, biliarystents, and the like. In an alternative embodiment, the radioactivestent may additionally comprise antithrombogenic agents. In oneembodiment, the radioactive stent is temporarily placed within the lumenof a vessel, for example a thin wire with a radioactive tip is placedwithin the bile duct, wherein the wire can be withdrawn after a limitedtime.

In preferred embodiments, the transition metal stent has a radioactivityof about 0.1 μCi to about 100 μCi, preferably of about 0.2 μCi to about90 μCi, and more preferably of about 0.5 μCi to about 80 μCi per stent;wherein about 1% to about 67%, preferably about, and more preferablyabout 1% to about 33% of the total surface comprises chemically boundphosphorus-31 and phosphorus-32 atoms. The chemically-boundphosphorous-32 is incorporated primarily on the surface of the stent, upto a depth of about 300A°, preferably about 200A°, most preferably 100A°from the surface of the stent.

In another embodiment, the transtion metal stent is microscopicallyroughened, using known procedures, prior to immersion in the emulsion.In an alternative embodiment, the transtion metal stent ismicroscopically roughened during immersion in the emulsion In apreferred embodiment, the transtion-metal stent is microscopicallyroughened in the upper stent surface. For example, the transition metalstent may be roughened by chemically etching the stent either prior tobeing placed in the emulsion, or the stent may be etched duringimmersion by the acidic emulsion. Generally, etching with chemicals,such as acid solutions, e.g., HCI solution, causes the surface to pitand roughen.

The following examples are illustrative in nature, and are not intendedto limit the scope of the present invention in any manner.

EXAMPLE 1

Metaphosphoric acid (HPO₃)_(n)(wherein n=3 or 4) is prepared accordingto known procedures. (See The Merck Index, 9^(th) Ed, 1976, page 956).Phosphorus-32 enriched 85% H₃PO₄ (0.5 ml) is heated in an open vessel ata temperature above 300° C. for approximately about 5 to 50 hours toyield the metaphosphoric acid having a radioactivity of about 1 mCi toabout 10,000 mCi per ml. Dimethylpolysiloxane polymer (Dow Corning,boiling point >200° C. and a kinematic viscosity of about 20 CS) (20 ml)is added to the metaphosphoric acid to form an emulsion. The emulsion isthen stabilized, with agitation, at about 150-200° C. A stent, such as astainless steel type 316L stent is completely immersed in the emulsionfor about 10-120 minutes, while being gently agitated so that it is inconstant contact with the acid globules. The stent is then removed fromthe emulsion, rinsed in boiling deionized water, rinsed again in roomtemperature deionized water, and dried using nitrogen gas. The stent isthen optionally immersed in a suitable non-polar solvent with a lowdielectric constant, such as n-hexane, chloroform, carbon tetrachloride,diethyl ether, and the like, to remove the residual polymer.

EXAMPLE 2

Radioactive stainless steel type 316 stents (1.9 cm²) (Alan Steel &Supply Co., Redwood City, Calif.) were produced according to theprocedure described in Example 1 above.

Metaphosphoric acid was prepared as follows. Orthophosphoric acid (4.5ml) was added to a vitreous carbon crucible (3.2 cm diameter, 4.6 cmdeep) housed in a temperature controlled copper block heater. Achromel-alumel thermocouple inserted in the copper block was used tomonitor the temperature and as a feedback loop for controllingtemperature. The copper block was incrementally heated over a period of45 minutes as follows: the temperature was raised to 153° C. in 10minutes; to 175° C. in 20 minutes; to 200° C. in 30 minutes; to 210° C.in 36 minutes and finally to 330° C. in 45 minutes. The copper block wasmaintained at 330° C. for 19 hours, to yield the metaphosphoric acid.

The temperature of the copper block was lowered to 215° C. in 10minutes. Dimethoxypolysiloxane polymer (Dow Corning 220 fluid, 20 CSkinematic viscosity) (4.9 ml) was then added to the crucible containingthe metaphosphoric acid and the emulsion was stabilized at 215° C. Thestainless steel type 316 stent was placed in the crucible and stirredperiodically for 30 minutes. The stent was removed from the emulsion andplaced in a pyrex beaker containing tap water (room temperature). Thestent was then rinsed under running tap water and dried. The stent wassubsequently dipped in n-hexane to remove any residual polymer.

FIG. 1 illustrates the X-ray photoelectron spectroscopy (XPS) sputterdepth profile for a radioactive stainless steel stent, wherein theatomic concentration (%) is plotted against the depth (nm) for theelements, P, Fe, O and Mo. The radioactive stent contains about 20%chemically-bound phosphorous, incorporated primarily on the surface ofthe stent, up to a depth of approximately 20 nm.

FIG. 2 illustrates the binding energy (eV) for the phosphorous 2p^(3/2)core-level transition measured according to standard procedures. Asevidenced from FIG. 2, all of the phosphorous is chemically bound: thepeak at 134 eV corresponds to the metaphosphate and the peak at 130 eVcorresponds to reduced phosphorous, i.e. phosphide.

Thus, a radioactive transition metal stent, comprising one or moretransition metals, wherein the transition metal stent surface ischemically bound to a radioactive material is disclosed. A method forproducing the radioactive transition metal stent wherein theradioisotope is chemically bound to, and uniformly confined to the stentsurface without affecting the metallurgical properties of the stent isalso disclosed. Although preferred embodiments of the invention havebeen described in some detail, it is understood that obvious variationscan be made without departing from the spirit and scope of the inventionas defined by the appended claims.

What is claimed is:
 1. A radioactive transition metal stent, comprisingone or more transition metals, wherein the transition metal stentsurface is chemically bound to a radioactive material, and furtherwherein the radioactive material comprises a metaphosphate or aphosphide surface.
 2. The radioactive transition metal stent of claim 1wherein the transition metal is a single element or an alloy of two ormore transition metals.
 3. The radioactive transition metal stent ofclaim 2, wherein the transition metals are selected from a groupconsisting of scandium, titanium, vanadium, chromium, manganese, iron,cobalt, nickel, copper, zinc, ytterbium, zirconium, niobium, molybdenum,silver, lanthanum, hafnium, tantalum, tungsten, rhenium, rare-earthelements, cerium, praseodymium, neodymium, promethium, samarium,europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium,yttrium, lutetium and rhodium.
 4. The radioactive transition metal stentof claim 2, wherein the transition metal is an alloy selected from agroup consisting of stainless-steel type 316, stainless-steel type 316L,a nickel-titanium alloy and a cobalt-nickel alloy.
 5. The radioactivetransition metal stent of claim 1 wherein the radioactive materialcomprises a metaphosphate surface wherein about 1% to about 67% of thetotal surface comprises chemically bound phosphorus-31 and phosphorus-32atoms.
 6. The radioactive transition metal stent of claim 5, wherein themetaphosphate surface comprises a radioactivity of about 0.1 μCi toabout 100 μCi per stent.
 7. The radioactive transition metal stent ofclaim 5 wherein said chemically-bound phosphorus-32 has a depth of about300 A° to about 100 A° from the surface of the stent.